612
J. Dong et al. / European Journal of Medicinal Chemistry 108 (2016) 605e615
DMSO-d6)
d
: 14.54 (br, 2H), 9.98 (s, 1H), 9.49 (s, 1H), 8.98 (s, 1H),
4.1.7.8. (1R,2R,3R,5S)-N-((2-cyclopropyl-1H-imidazol-5-yl)methyl)-
2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine hydrochloride (37).
White powder, yield: 51.3%, mp 260e262 ꢀC. 1H NMR (400 MHz,
4.35 (s, 2H), 3.53 (s, 1H), 2.44e2.35 (m, 1H), 2.32e2.18 (m, 3H),
2.06e1.97 (m, 2H), 1.81 (s, 1H), 1.42 (d, J ¼ 10 Hz, 1H), 1.26e1.15 (m,
7H), 1.03 (d, J ¼ 7.6 Hz, 2H), 0.93 (s, 4H); 13C NMR (126 MHz, DMSO-
DMSO-d6) d: 14.61 (br, 2H), 9.90 (s, 1H), 9.55 (s, 1H), 7.65 (s, 1H),
d6)
d: 135.35, 133.83, 121.04, 56.25, 47.41, 40.76, 38.83, 32.29, 31.03,
4.26 (s, 2H), 3.43e3.32 (m Hz,1H), 2.44e2.24 (m, 3H), 2.21e2.12 (m,
1H), 2.05e1.93 (m, 2H), 1.80 (t, J ¼ 5.2 Hz, 1H),1.39 (d, J ¼ 10 Hz, 1H),
1.28e1.23 (m, 2H), 1.23e1.19 (m, 5H), 1.18 (d, J ¼ 7.2 Hz, 3H), 0.92 (s,
27.68, 23.66, 21.13, 7.93, 7.77, 5.60. HRMS calcd for C17H27N3
[M þ H]þ, 274.2278, found, 274.2278.
3H); 13C NMR (126 MHz, DMSO-d6)
d: 149.38, 123.42, 119.31, 55.59,
4.1.7.3. (1R,2R,3R,5S)-N-((4-(tert-butyl)-1H-imidazol-5-yl)methyl)-
46.98, 40.28, 38.35, 38.07, 31.75, 30.61, 27.21, 23.27, 20.71, 9.39, 6.90.
2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine
Light yellow powder, yield: 10.1%, mp 130e132 ꢀC. 1H NMR
(400 MHz, DMSO) : 14.65 (br, 2H), 10.14 (s, 1H), 9.48 (s, 1H), 9.16 (s,
hydrochloride(32).
HRMS calcd for C17H27N3 [M þ H]þ, 274.2278; found, 274.2276.
d
4.1.7.9. (1R,2R,3R,5S)-N-((2-isopropyl-1H-imidazol-5-yl)methyl)-
2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine hydrochloride (38).
Whiter powder, yield: 56.7%, mp 178e180 ꢀC. 1H NMR (400 MHz,
1H), 8.19 (s, 1H), 4.39 (s, 2H), 2.42 (t, J ¼ 11.2 Hz, 1H), 2.33e2.19 (m,
2H), 2.09e1.95 (m, 2H),1.81 (t, J ¼ 5.2 Hz,1H),1.50 (d, J ¼ 10 Hz,1H),
1.43 (s, 9H), 1.23e1.19 (m, 6H), 0.95 (s, 3H); 13C NMR (126 MHz,
DMSO-d6) d: 14.78 (br, 2H), 10.00 (s, 1H), 9.65 (s, 1H), 7.75 (s, 1H),
DMSO-d6)
d
: 140.15, 134.14, 119.14, 57.02, 47.48, 40.82, 38.90, 32.59,
4.32 (s, 2H), 3.50e3.41 (m, 1H), 3.40e3.28 (m, 1H), 2.39 (t,
J ¼ 12.0 Hz, 1H), 2.33e2.24 (m, 1H), 2.23e2.14 (m, 1H), 2.07e1.99
(m, 1H), 1.96 (s, 1H), 1.80 (t, J ¼ 5.2 Hz, 1H), 1.40 (d, J ¼ 10.0 Hz, 1H),
1.38 (s, 3H), 1.36 (s, 3H), 1.21 (s, 3H), 1.19 (d, J ¼ 7.2 Hz, 3H), 0.92 (s,
32.24, 31.03, 30.08, 27.73, 23.68, 21.17. HRMS calcd for C18H31N3
[M þ H]þ, 290.2590; found, 290.2591.
4.1.7.4. (1R,2R,3R,5S)-N-((4-propyl-1H-imidazol-5-yl)methyl)-2,6,6-
trimethylbicycle[3.1.1]heptan-3-amine hydrochloride (33). Pale yel-
low powder, yield: 15.3%, mp 217e219 ꢀC. 1H NMR (400 MHz,
3H); 13C NMR (126 MHz, DMSO-d6)
d: 152.37, 124.27, 120.06, 56.08,
47.45, 40.74, 38.82, 38.59, 32.23, 31.07, 27.67, 26.66, 23.72, 21.18,
20.75. HRMS calcd for C17H29N3 [M þ H]þ, 276.2434; found,
276.2435.
DMSO-d6) d: 14.62 (br, 1H), 9.93 (s, 1H), 9.44 (s, 1H), 9.02 (s, 1H),
4.30 (s, 2H), 3.53 (s, 1H), 2.73 (t, J ¼ 7.2 Hz, 2H), 2.37 (t, J ¼ 11.2 Hz,
1H), 2.32e2.25 (m, 1H), 2.20 (t, J ¼ 6.4 Hz, 1H), 2.07e2.02 (m, 1H),
1.97 (s, 1H), 1.81 (d, J ¼ 5.6 Hz, 1H), 1.69e1.60 (m, 2H), 1.42 (d,
J ¼ 10.0 Hz, 1H), 1.23e1.15 (m, 7H), 0.92e0.89 (m, 6H); 13C NMR
4.1.7.10. (1R,2R,3R,5S)-N-((2-(tert-butyl)-1H-imidazol-5-yl)methyl)-
2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine hydrochloride (39).
White powder, yield: 44.6% mp 189e191 ꢀC. 1H NMR (400 MHz,
(126 MHz, DMSO-d6)
d: 134.25, 133.79, 120.71, 56.39, 47.46, 40.77,
DMSO-d6) d: 14.76 (br, 2H), 10.04 (s, 1H), 9.66 (s, 1H), 7.75 (s, 1H),
38.81, 37.81, 32.26, 31.04, 27.67, 25.31, 23.64, 22.26, 21.17, 13.75.
4.35 (s, 2H), 3.44e3.30 (m, 1H), 2.39e2.27 (m, 2H), 2.23e2.13 (m,
1H), 2.04e1.97 (m, 2H), 1.80 (t, J ¼ 5.2 Hz, 1H), 1.45 (s, 9H), 1.38 (d,
HRMS calcd for C17H29N3 [M þ H]þ, 276.2434; found, 276.2432.
J ¼ 10.0 Hz, 1H), 1.21 (s, 3H), 1.19 (d, J ¼ 5.0 Hz, 3H), 0.92 (s, 3H); 13
C
4.1.7.5. (1R,2R,3R,5S)-N-((4-phenyl-1H-imidazol-5-yl)methyl)-2,6,6-
NMR (126 MHz, DMSO-d6) d: 155.22, 120.78, 56.68, 55.80, 49.63,
trimethylbicycle[3.1.1]heptan-3-amine
White powder, yield: 13.6%, mp 156e158 ꢀC. 1H NMR (400 MHz,
DMSO-d6) : 10.12 (s, 1H), 9.57 (s, 1H), 9.16 (s, 1H), 7.79e7.68 (m,
hydrochloride
(34).
47.91, 47.81, 42.26, 41.32, 41.20, 39.27, 39.07, 33.86, 33.71, 33.41,
32.74, 31.57, 29.13, 28.34, 28.14, 24.17, 24.06, 21.66, 21.06. HRMS
calcd for C18H31N3 [M þ H]þ, 290.2591; found, 290.2593.
d
2H), 7.60e7.52 (m, 3H), 4.41 (s, 2H), 3.53 (s, 1H), 2.32e2.10 (m, 3H),
1.98e1.92 (m, 2H), 1.83e1.72 (m, 1H), 1.42 (d, J ¼ 10 Hz, 1H), 1.18 (s,
3H), 1.12 (d, J ¼ 7.2 Hz, 3H), 0.84 (s, 3H); 13C NMR (126 MHz, DMSO-
4.1.7.11. (1R,2R,3R,5S)-N-((2-isobutyl-1H-imidazol-5-yl)methyl)-
2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine hydrochloride (40).
White powder, yield: 63.5%, mp 159e161 ꢀC. 1H NMR (400 MHz,
d6) d: 135.19, 132.30, 130.04, 129.55, 129.03, 126.91, 121.44, 56.31,
47.41, 40.78, 40.59, 38.81, 38.67, 32.25, 30.79, 27.68, 23.61, 21.05.
DMSO-d6) d: 14.82 (br, 2H), 10.04 (s, 1H), 9.66 (s, 1H), 7.77 (s, 1H),
HRMS calcd for C20H27N3 [M þ H]þ, 310.2278; found, 310.2276.
4.34e4.24 (m, 2H), 2.82 (d, J ¼ 7.2 Hz, 2H), 2.40 (t, J ¼ 12.4 Hz, 1H),
2.28 (s, 1H), 2.19e2.14 (m, 2H), 2.02e1.91 (m, 2H), 1.80 (t, J ¼ 5.2 Hz,
1H), 1.40 (s, 1H), 1.20 (s, 3H), 1.16 (d, J ¼ 7.2 Hz, 3H), 0.92 (s, 3H), 0.91
4.1.7.6. (1R,2R,3R,5S)-N-((2-methyl-1H-imidazol-5-yl)methyl)-2,6,6-
trimethylbicycle[3.1.1]heptan-3-amine
White powder, yield: 51.2%, mp 201e203 ꢀC. 1H NMR (400 MHz,
DMSO-d6) : 14.77 (br, 2H), 10.11 (s, 1H), 9.71 (s, 1H), 7.75 (s, 1H),
hydrochloride
(35).
(s, 6H); 13C NMR (126 MHz, DMSO-d6)
d: 146.94, 124.38, 120.21,
55.88, 47.43, 40.75, 38.84, 38.49, 34.11, 32.26, 31.01, 27.87, 27.69,
23.72, 22.25, 22.22, 21.12. HRMS calcd for C18H31N3 [M þ H]þ,
290.2591, found, 290.2591.
d
4.44e4.07 (m, 2H), 2.60 (s, 3H), 2.43e2.36 (m, 1H), 2.31e2.23 (m,
1H), 2.22e2.12 (m, 1H), 2.01 (ddd, J ¼ 14.0, 6.0, 2.4 Hz, 1H), 1.96 (s,
1H), 1.79 (t, J ¼ 5.2 Hz, 1H), 1.44 (d, J ¼ 10.0 Hz, 1H), 1.20 (s, 3H), 1.17
4.1.7.12. (1R,2R,3R,5S)-N-((2-butyl-1H-imidazol-5-yl)methyl)-2,6,6-
(d, J ¼ 7.2 Hz, 3H), 0.91 (s, 3H); 13C NMR (126 MHz, DMSO-d6)
d
:
trimethylbicyclo[3.1.1]heptan-3-amine
White powder, yield: 44.0%, mp 188e190 ꢀC. 1H NMR (400 MHz,
DMSO-d6) : 14.73 (br, 2H), 10.01 (s, 1H), 9.63 (s, 1H), 7.74 (s, 1H),
hydrochloride
(41).
144.24, 124.13, 120.16, 55.90, 47.45, 40.76, 38.84, 38.49, 32.17, 30.99,
27.69, 23.76, 21.16, 11.56. HRMS calcd for C15H25N3 [M þ H]þ,
248.2121; found, 248.2120.
d
4.41e4.09 (m, 2H), 2.94 (t, J ¼ 7.2 Hz, 2H), 2.40 (t, J ¼ 11.2 Hz, 1H),
2.31e2.26 (m, 1H), 2.22e2.13 (m, 1H), 2.02e1.96 (m, 2H), 1.80 (t,
J ¼ 5.2 Hz, 1H), 1.74 (m, (t, J ¼ 7.2 Hz, 2H), 1.40 (d, J ¼ 10 Hz, 1H),
1.36e1.24 (m, 2H), 1.20 (s, 3H), 1.17 (d, J ¼ 7.2 Hz, 3H), 0.95e0.85 (m,
4.1.7.7. (1R,2R,3R,5S)-N-((2-ethyl-1H-imidazol-5-yl)methyl)-2,6,6-
trimethylbicyclo[3.1.1]heptan-3-amine hydrochloride (36). Light
yellow powder, yield: 53.6%, mp 227e229 ꢀC. 1H NMR (400 MHz,
6H); 13C NMR (126 MHz, DMSO-d6)
d: 150.03, 126.37, 122.34, 58.12,
DMSO-d6)
d
: 14.77 (br, 2H), 10.04 (s, 1H), 9.66 (s, 1H), 7.75 (s, 1H),
49.65, 42.96, 41.03, 40.66, 34.43, 33.20, 31.21, 29.88, 27.30, 25.92,
23.91, 23.34, 15.95. HRMS calcd for C18H31N3 [M þ H]þ, 290.2591;
found, 290.2592.
4.40e4.15 (m, 2H), 2.96 (q, J ¼ 7.6 Hz, 2H), 2.39 (t, J ¼ 12 Hz, 1H),
2.32e2.23 (m, 1H), 2.22e2.13 (m, 1H), 2.06e1.98 (m, 1H), 1.96 (s,
1H),1.80 (t, J ¼ 5.2 Hz,1H),1.42 (d, J ¼ 10.0 Hz,1H), 1.33 (t, J ¼ 7.6 Hz,
3H), 1.20 (s, 3H), 1.18 (d, J ¼ 7.2 Hz, 3H), 0.92 (s, 3H); 13C NMR
4.1.7.13. (1R,2R,3R,5S)-N-((2-cyclopentyl-1H-imidazol-5-yl)methyl)-
2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine hydrochloride (42).
White solid, yield: 46.1%, mp 173e175 ꢀC. 1H NMR (400 MHz,
(126 MHz, DMSO-d6) d: 148.54, 123.77, 119.63, 55.57, 46.97, 40.28,
38.36, 38.12, 31.76, 30.61, 27.21, 23.27, 20.69, 18.89, 11.20. HRMS
calcd for C16H27N3 [M þ H]þ, 262.2278; found, 262.2278.
DMSO-d6) d: 14.74 (br, 2H), 9.95 (s,1H), 9.61 (s,1H), 7.72 (s,1H), 4.30